WM is a rare indolent low-grade B-cell lymphoma that remains incurable with a median overall survival of 5-6 years, and most patients succumb to disease progression. However, the survival and outcome of therapy in patients with WM varies widely and the 5-year survival of patients with WM may range from 36% in high risk WM to 87% in low risk patients based on the International Prognostic Scoring System (IPSS) in WM. Therefore, development of novel therapeutics that improve the outcome in patients with this disease is critical, but more importantly the design of specifically tailored therapies based on risk stratification may improve responses in these patients and decrease unwarranted toxicity in low-risk patients. The PI3K/mTOR and NF-kB pathways act as critical regulators of apoptosis, cell cycle, and tumor proliferation in lymphoproliferative disorders. Preliminary data indicate that Akt and NF-kB are activated in WM cells. This activation may be due to genetic or epigenetic aberrations or due to external stimulation by the bone marrow microenvironment. RAD001 and bortezomib/rituximab showed high activity in Phase 2 clinical trials in WM and the preclinical studies of the combination of these agents shows high cytotoxic activity in vitro and inhibits signaling through the PI3K/mTOR and NF-KB pathways. Based on these findings, the applicant hypothesizes that activation of the PI3K and NF-kB pathways through constitutive regulation or external stimulation by the bone marrow milieu leads to resistance to therapy. The applicant proposes that activation of these pathways may be due to 1) constitutive activation within malignant cells or 2) external stimulation through the bone marrow microenvironment. This proposed hypothesis is to be tested in 3 aims: Aim 1 is to examine in vivo activity and safety of the combination of RAD001/rituximab or RAD001/bortezomib/rituximab in a Phase 1/2 clinical trial based on risk-stratification of patients according to the IPSS-WM staging system. The clinical trial will include a Phase 1 study to determine the maximum tolerated dose (MTD) of the combination of AD001/rituximab and RAD001/rituximab/bortezomib. This will be followed by a Phase 2 trial with 2 arms. Arm A will include patients with low risk WM based on the IPSS stating system where patients will receive the combination of RAD001 and rituximab. Arm B will include patients with intermediate-high risk WM where patients will receive the combination of RAD001/bortezomib/rituximab. The primary objective of these Phase 2 studies is to assess the depth of response in patients with WM. Aim 2 is to determine genetic and epigenetic regulators of the PI3K and NF-kB pathways and their role in resistance to therapy in WM, and Aim 3 is to identify the role of the bone marrow microenvironment in conferring resistance to therapy through the PI3K and NF-kB pathways. Although rare, WM is more homogenous in its biological aberrations compared to other lymphoproliferative disorders, and therefore, it may become a model disease for other low-grade lymphomas and plasma cell dyscrasias where aberrant molecular pathways are identified and functionally validated using novel therapeutic agents.